What to Test in Parkinson Disease Prevention Trials? Repurposed, Low-Risk, and Gene-Targeted Drugs.
What to Test in Parkinson Disease Prevention Trials? Repurposed, Low-Risk, and Gene-Targeted Drugs.
复制标题
DOI：
10.1212/wnl.0000000000200238
复制
发表时间：
2022-08-16
期刊：
影响因子：
9.9
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管在显性帕金森病（PD）中进行的许多“疾病修饰”试验都有合理的流行病学和基础科学依据，但没有一项令人信服地证明治疗可以减缓进展。快速扩大知识的遗传决定因素和前驱特征的PD现在允许现实规划的预防试验，在疾病的早期开始puerestine神经保护治疗。在本文中，我们概述了PD预防试验的药物选择原则，重点是概念验证机会，这将有助于为这个新兴领域建立方法学基础。我们描述了用于此类试验的原型，相对低风险的候选药物（例如，沙丁胺醇、氨溴索、咖啡因、布洛芬），适用于特定的高危人群，从致病性LRRK 2或GBA基因变异携带者到前驱PD和α-突触核蛋白病定义的人群。最后，我们回顾了目前正在开发的针对临床表现PD的基因靶向方法，以了解其在未来预防试验中的潜力。
Despite the sound epidemiologic and basic science rationales underpinning numerous “disease modification” trials in manifest Parkinson disease (PD), none has convincingly demonstrated that a treatment slows progression. Rapidly expanding knowledge of the genetic determinants and prodromal features of PD now allows realistic planning of prevention trials with initiation of putatively neuroprotective therapies earlier in the disease. In this article, we outline the principles of drug selection for PD prevention trials, focused on proof-of-concept opportunities that will help establish a methodological foundation for this fledgling field. We describe prototypical, relatively low-risk drug candidates for such trials (e.g., albuterol, ambroxol, caffeine, ibuprofen), tailored to specific at-risk populations ranging from pathogenic LRRK2 or GBA gene variant carriers to those defined by prodromal PD and α-synucleinopathy. Finally, we review gene-targeted approaches currently in development targeting clinically manifest PD for their potential in future prevention trials.